Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell-transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice.

Purpose Ovarian cancer has a high recurrence and mortality rate. A barrier to improved outcomes includes a lack of accurate models for preclinical testing of novel therapeutics. Experimental Design Clinically-relevant, patient-derived tumorgraft models were generated from sequential patients and the first 168 engrafted models are described. Fresh ovarian, primary peritoneal, and fallopian tube carcinomas were collected at the time of debulking surgery and injected intraperitoneally into severe combined immunodeficient mice. Results Tumorgrafts demonstrated a 74% engraftment rate with microscopic fidelity of primary tumor characteristics. Low-passage tumorgrafts also showed comparable genomic aberrations with the corresponding primary tumor and exhibit gene set enrichment of multiple ovarian cancer molecular subtypes, similar to patient tumors. Importantly, each of these tumorgraft models are annotated with clinical data and for those that have been tested, response to platinum chemotherapy correlates with the source patient. Conclusions Presented herein is the largest known living tumor bank of patient-derived, ovarian tumorgraft models that can be applied to the development of personalized cancer treatment.

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Estrogens play a crucial role in the causation and development of sporadic human breast cancer (BC). Chromosomal instability (CIN) is a defining trait of early human ductal carcinoma in situ (DCIS) and is believed to precipitate breast oncogenesis. We reported earlier that 100% of female ACI (August͞Copenhagen͞Irish) rats treated with essentially physiological serum levels of 17␤-estradiol lead to mammary gland tumors with histopathologic, cellular, molecular, and ploidy changes remarkably similar to those seen in human DCIS and invasive sporadic ductal BC. Aurora-A (Aur-A), a centrosome kinase, and centrosome amplification have been implicated in the origin of aneuploidy via CIN. After 4 mo of estradiol treatment, levels of Aur-A and centrosomal proteins, ␥-tubulin and centrin, rose significantly in female ACI rat mammary glands and remained elevated in mammary tumors at 5-6 mo of estrogen treatment. Centrosome amplification was initially detected at 3 mo of treatment in focal dysplasias, before DCIS. At 5-6 mo, 90% of the mammary tumor centrosomes were amplified. Comparative genomic hybridization revealed nonrandom amplified chromosome regions in seven chromosomes with a frequency of 55-82% in 11 primary tumors each from individual rats. Thus, we report that estrogen is causally linked via estrogen receptor ␣ to Aur-A overexpression, centrosome amplification, CIN, and aneuploidy leading to BC in susceptible mammary gland cells. More than 90% of all human breast cancer (BC) cases are sporadic (1). Numerous epidemiological and animal studies show that both endogenous and exogenously ingested estrogens (Es) play a central, if not paramount, role in the causation and development of human sporadic BC (2-6). Recent epidemiological studies show only a minimal rise in BC risk in postmenopausal women taking E replacement therapy over varying periods of use (7-9). In premenopausal women, however, all of the well established risk factors clearly implicate Es in the causation of BC (2-6). In this latter group, 17␤-estradiol (E 2 ) concentrations, all in the low picogram range, within narrow limits of serum and breast tissue levels (10-13), are sufficient to increase sporadic BC risk. Therefore, it is essential to gain a better understanding of how Es, at these physiological concentrations, elicit their oncogenic effects in susceptible target tissues.Chromosomal instability (CIN) and aneuploidy are defining traits of early human BC ductal carcinoma in situ (DCIS) and primary invasive ductal BCs. These distinguishing characteristics of human BC have been seen in 55-78% of the DCISs and in 85-92% of invasive ductal BCs (14-17). Aneuploidy has been a reliable biomarker for BC for many decades. However, it has not been realized until now that it provides an important clue to the causation of sporadic human BC and the involvement of Es in its etiology.Overexpression of a centrosome kinase, Aurora-A (Aur-A), centrosome amplification, and CIN invariably occur together (18,19). Centrosome amplification, found in human BC, may play...

The insulin-like growth factor pathway plays a major role in cancer cell proliferation, survival and resistance to anti-cancer therapies in many human malignancies, including breast cancer. As a key signaling component of IGF system, the IGF-1 receptor is the target of several investigational agents in clinical and pre-clinical development. This review will focus on the rationale for targeting the IGF-1 receptor and other components of the IGF-1 system. In addition, we will examine the role of IGF-1 signaling in resistance to clinically important breast cancer therapies, including cytotoxic chemotherapy, hormonal therapy and erbB targeted agents. We will also review the completed and ongoing clinical investigations with IGF-1 receptors inhibitors to date and the utility of these early data in designing future breast cancer studies with IGF-1 signaling inhibition strategies. KeywordsReceptor; IGF Type I; IGF-1R inhibition; Monoclonal antibody; Tyrosine kinase inhibitors; Clinical trials-Phase I; Clinical trials-Phase II; Drug resistance; Receptor crosstalk Therapeutic Potential of Targeting IGF Signaling IGF system as a drug targetTargeting the IGF signaling pathway represents a promising strategy in the development of novel anti-cancer therapeutics. As a drug target, the IGF system has a number of key features that lends itself to being appealing. The expression of IGF-1R, the major signal transducing receptor of the pathway, appears to be necessary for malignant transformation in preclinical models [1]. Indeed, forced overexpression of IGF-1R increases the timing and frequency of tumor development in animal models [2,3]. Also, IGF-1 deficient mice have greatly reduced capacity to support tumor growth and metastasis [4].An important feature of the IGF system is its near ubiquitous presence in most solid and hematologic malignancies, including expression of the IGF-1R [5]. In breast cancer in particular, the expression of IGF-1R may approach 90% [6,7]. Compared to HER2 + breast cancers, which represent 20-25% of all breast cancers, this represents a much broader potential group of patients that may be candidates for targeted therapy. In addition to IGF-1R, there are also several components of the system, including activating ligands IGF-1 and IGF-II, that may serve as 'druggable' targets, allowing various approaches to be evaluated for clinical activity. Whether or not, however, the IGF system, which is important for a number of normal physiologic processes, is dispensable in normal tissues to the extent that signaling can be attenuated to allow anti-tumor activity it less clear. In addition to the critical importance of IGF system signaling on growth and development, several key physiologic functions including NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript energy systems integration, glucose/insulin regulation, mammary development and lactation, bone health, neuronal maintenance [8,9]. While these processes are tightly regulated in normal tissues (described elsewhere in this i...

Patient-derived tumor xenograft (PDX) mouse models have emerged as an important oncology research platform to study tumor evolution, mechanisms of drug response and resistance, and tailoring chemotherapeutic approaches for individual patients. The lack of robust standards for reporting on PDX models has hampered the ability of researchers to find relevant PDX models and associated data. Here we present the PDX models Minimal Information standard (PDX-MI) for reporting on the generation, quality assurance and use of PDX models. PDX-MI defines the minimal information for describing the clinical attributes of a patient’s tumor, the processes of implantation and passaging of tumors in a host mouse strain, quality assurance methods, and the use PDX models in cancer research. Adherence to PDX-MI standards will facilitate accurate search results for oncology models and their associated data across distributed repository databases and promote reproducibility in research studies using these models.

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Summary A genome-wide association study identified LMO1, which encodes a LIM-domain-only transcriptional cofactor, as a neuroblastoma susceptibility gene that functions as an oncogene in high-risk neuroblastoma. Here we show that dβh promoter-mediated expression of LMO1 in zebrafish synergizes with MYCN to increase the proliferation of hyperplastic sympathoadrenal precursor cells, leading to a reduced latency and increased penetrance of neuroblastomagenesis. The transgenic expression of LMO1 also promoted hematogenous dissemination and distant metastasis, which was linked to neuroblastoma cell invasion and migration, and elevated expression levels of genes affecting tumor cell-extracellular matrix interaction, including loxl3, itga2b, itga3 and itga5. Our results provide in vivo validation of LMO1 as an important oncogene that promotes neuroblastoma initiation, progression, and widespread metastatic dissemination.